Calcium phosphate bone replacement materials and methods of use thereof

ABSTRACT

Methods of making porous calcium phosphate bone replacement materials are discussed.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationSerial No.: 60/342,622, filed Dec. 21, 2001, entitled “Calcium PhosphateBone Replacement Materials and Methods of Use Thereof.” The entirecontents of the aforementioned application are hereby incorporatedherein by reference in its entirety.

BACKGROUND

[0002] Trauma, pathological degeneration, or congenital deformity mayresult in the need for surgical reconstruction or replacement of bonetissue. Reconstructive surgery is based upon the principle of replacingdefective bone tissue with viable, functioning alternatives. In skeletalapplications, surgeons have historically used bone grafts. The two maintypes of bone grafts currently used are autografts and allografts. Anautograft is a section of bone taken from the patient's own body, whilean allograft is taken from a cadaver. This method of grafting providesthe defect site with structural stability and natural osteogenicbehavior. However, both types of grafts are limited by certainuncontrollable factors. For autografts, the key limitation is donor sitemorbidity where the remaining tissue at the harvest site is damaged byremoval of the graft. Other considerations include the limited amount ofbone available for harvesting, and unpredictable resorptioncharacteristics of the graft. The main limitation of allografts has beenthe immunologic response to the foreign tissue of the graft. The tissueis often rejected by the body and is subject to the inflammatoryresponse. Allografts are also capable of transmitting disease. Althougha thorough screening process eliminates most of the disease carryingtissue, this method is not 100% effective.

[0003] Conventional orthopedic implants such as screws, plates, pins androds serve as loadbearing replacements for damaged bone and are usuallycomposed of a metal or alloy. Although these implants are capable ofproviding rigid fixation and stabilization of the bone, they causeimproper bone remodeling of the implant site due to the large differencein the modulus between bone and metal.

[0004] These limitations have initiated the search for a dependablesynthetic bone graft substitute. However, in order for an implant to beused as a replacement for bone, it must be capable of bothosteointegration and osteoconduction. Osteointegration refers to directchemical bonding of a biomaterial to the surface of bone without anintervening layer of fibrous tissue. This bonding is referred to as theimplant-bone interface. A primary problem with skeletal implants ismobility. Motion of the implant not only limits its function, but alsopredisposes the implant site to infection and bone resorption. With astrong implant-bone interface, however, mobility is eliminated, thusallowing for proper healing to occur. Osteoconduction refers to theability of a biomaterial to sustain cell growth and proliferation overits surface while maintaining the cellular phenotype. For osteoblasts,the phenotype includes mineralization, collagen production, and proteinsynthesis. Normal osteoblast function is particularly important forporous implants that require bone ingrowth for proper strength andadequate surface area for bone bonding.

[0005] Calcium phosphate-based materials have been investigated for useas bone replacement materials. Most calcium phosphate biomaterials arepolycrystalline ceramics characterized by a high biocompatibility, theability to undergo osteointegration, and varying degrees ofresorbability. Implants made from these materials can be in either aporous or non-porous form. Examples of commercially available calciumphosphate materials include Interpore 200 and Interpore 500. Surgicalmodels using previously developed porous calcium phosphate-based implantmaterials, however, have shown that porous implants heal more slowlythan both autografts and empty defects (Nery et al. J. Periodotol. 197546:328; Levin et al. J. Biomed. Mat. Res. 1975 9:183). Studies on tissueingrowth in non-resorbable implants have also shown that failure oftissue to completely fill the implant can lead to infection (Feenstra,L. and De Groot, K. “Medical use of calcium phosphate ceramics” InBioceramics of Calcium Phosphate, De Groot, K. Ed., CRC Press, BocaRaton, Fla., 1983, pp 131-141; Feldman, D. and Esteridge, T.Transactions 2nd World Congress Biomaterials Society, 10th AnnualMeeting, 1984, p 37).

[0006] Implants synthesized from the calcium phosphate-based material,hydroxyapatite (HA), the major mineral constituent of bone, arecommercially available in a porous and non-porous form. Synthetic HAimplants have excellent biocompatibility. Blocks of dense HA are notuseful in reconstructive surgery because they are difficult to shape anddo not permit tissue ingrowth. However, in a non-porous, particulateform, HA has been used successfully in both composite (Collagraft) andcement (Hapset) forms (Chow et al. Mater. Res. Soc. Symp. Proc. 1993179:3-24; Cornell, C. N. Tech. Orthop. 1992 7:55). Due to its fragilityand lack of compliance, porous HA have been largely limited to dentaland maxillofacial surgery.

SUMMARY OF THE INVENTION

[0007] In one embodiment, the invention pertains, at least in part, to amethod of producing a porous calcium phosphate material. The methodincludes forming a mixture of calcium ions and phosphate ions having acalcium to phosphorus ratio of 0.1 to 1.67, heating the mixture to anappropriate reaction temperature, and cooling the reaction mixture.

[0008] In another embodiment, the invention pertains, at least in part,to a method of producing a porous calcium phosphate material. The methodincludes forming a mixture of calcium ions and phosphate ions, having acalcium to phosphorus ratio of 0.1 to 1.67, adding a gas-generatingmaterial to the mixture, heating said mixture an appropriatetemperature, and cooling the mixture. Preferably, the porous calciumphosphate material produced has interconnected pores.

[0009] In another embodiment, the invention also pertains to anothermethod of producing a porous calcium phosphate material. The methodincludes mixing a gas-generating material and a calcium phosphateceramic precursor, heating the mixture to below the sinteringtemperature to generate a gas, and sintering the calcium phosphateceramic precursors to make solid ceramic materials.

[0010] In another embodiment, the invention pertains to yet anothermethod of producing a calcium phosphate material. This method includes 1subliming a solid chemical in a reactive calcium phosphate mixture orcalcium phosphate ceramic precursor, and before undergoing the chemicalreaction or sintering the calcium phosphate ceramic precursor.

[0011] The invention also pertains, at least in part, to surgicalimplants which contain a calcium phosphate material produced by themethods of the invention.

[0012] In another, embodiment, the invention also pertains to syntheticcalcium phosphate material produced by the methods of the invention. Ina further embodiment, the calcium phosphate material generated by themethods of the invention is biodegradable.

[0013] In a further embodiment, the invention also pertains to a methodof treating of bone disorder in a subject. The method includes applyinga calcium phosphate material of the invention to a bone of said subject,such that the bone disorder of said subject is treated.

[0014] In another embodiment, the invention also pertains to a calciumphosphate material, comprising the calcium salt of:

[0015] wherein n is an integer between 10 and 1,000,000.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1a is a SEM image of the control calcium phosphate materialat 26.4 magnification.

[0017]FIG. 1b is a SEM image of the calcium phosphate material withusing 15% ammonium bicarbonate (particle size greater than 425 μm) at20×magnification.

[0018]FIG. 1c is an image of the calcium phosphate material with 20%ammonium bicarbonate (particle size less than 106 μm) at a26.4×magnification.

[0019]FIG. 1d is a SEM image of the calcium phosphate material with 20%ammonium bicarbonate (particle size between 212-250 μm) at a26.4×magnification.

[0020]FIG. 1e is a SEM image of the calcium phosphate material with 20%ammonium bicarbonate (particle size between 250 and 425 μm) at a26.4×magnification.

[0021]FIG. 1f is a SEM image of the calcium phosphate material with 20%ammonium bicarbonate (particle size between 250 and 425 μm)at a50.5×magnification.

[0022]FIG. 1g is a SEM image of the calcium phosphate material with 25%ammonium bicarbonate (particle size between 125 and 250) at a26.4×magnification.

[0023]FIG. 2 is a histogram which shows the frequency of pore diametersfor control calcium phosphate material (without gas-generatingmaterial), calcium phosphate made with 20% of a gas-generating material,and calcium phosphate material made with 25% of a gas-generatingmaterial.

DETAILED DESCRIPTION OF THE INVENTION

[0024] A new synthetic calcium phosphate material has been developed.The size, shape and porosity can be both predetermined and controlled inthe synthetic process. Pore size and density are important in promotingtissue ingrowth. Both the nonporous and porous materials demonstratehigh flexural and compressive strength compared to the other availableceramics and are comparable to autologous bone. This material is a purecalcium phosphate devoid of contaminants such as silicates, zinc andalumina which may possibly retard osteogenesis.

[0025] In one embodiment, the invention pertains to a method ofproducing calcium phosphate material. The method includes forming amixture of calcium ions and phosphate ions having a calcium tophosphorus ratio of 0.1 to 1.67, heating the mixture to an appropriatereaction temperature; and cooling the reaction mixture. The ratio ofcalcium to phosphate ions is preferably selected such that the resultingmaterial is able to perform its intended function. For convenience, thecalcium to phosphate ion ratio is abbreviated as the “Ca/P ratio.”

[0026] The term “calcium phosphate material” includes synthetic materialcomprised of calcium and phosphate ions and, advantageously,non-apatitic. Preferably, the material is synthesized by the methods ofthe invention and is suitable for its intended purpose, e.g., as a bonereplacement. The calcium phosphate material of the invention,advantageously, is porous. The pores may or may not be interconnected.

[0027] In a further embodiment, the Ca/P ration is about 0.20 to about0.80, about 0.25 to about 0.75, about 0.30 to about 0.70, about 0.35 toabout 0.65, about 0.40 to about 0.60, about 0.40 to about 0.55, about0.45 to about 0.50, about 0.46 to about 0.50, about 0.47 to about 0.50,about 0.475 to about 0.495, about 0.480 to about 0.490, or about 0.486.Advantageously the Ca/P ratio is selected on the basis of advantageousbiocompatibility and strength.

[0028] The calcium ions may be obtained from any source known in theart. Examples of sources of calcium ions that may be used includeapatitic calcium phosphates, non-apatitic calcium phosphates, calciumhydroxide, calcium oxide, calcium carbonate, calcium salts, calciumhalide, calcium metal, and combinations thereof. In certain embodiments,the calcium ion source is hydroxyapatite.

[0029] The phosphate ions may also be obtained from any source known inthe art. Examples of sources of phosphate ions include, but are notlimited to, orthophosphoric acid, pyrophosphoric acids, condensedphosphates, phosphate of non-metal cations, metal phosphates, andcombinations thereof. In certain embodiments, the phosphate ion sourceis orthophosphoric acid.

[0030] In an embodiment, the invention pertains to a calcium phosphatematerial of the invention having a 0.486 Ca/P ratio, synthesized fromhydroxyapatite and orthophosphoric acid.

[0031] The calcium phosphate material is, generally, a highly porousmaterial with average pore sized ranging from, for example, about 5 μmto about 1000 μm or greater. In an embodiment, the pore size averagesabout 50 μm. In other embodiments, the pore size averages between about20 μm and about 200 μm, about 20 μm and about 190 μm, about 20 μm andabout 180 μm, about 20 μm and about 170 μm, about 20 μm and about 160μm, about 20 μm and about 150 μm, about 20 μm and about 140 μm, about 20μm and about 130 μm, about 20 μm and about 130 μm, about 20 μm and about120 μm, about 20 μm and about 110 μm, about 20 μm and about 100 μm,about 20 μm and about 90 μm, about 20 μm and about 80 μm, about 20 μmand about 75 μm, about 20 μm and about 70 μm, about 20 μm and about 65μm, about 20 μm and about 60 μm, about 25 μm and about 60 μm, about 30μm and about 60 μm, about 35 μm and about 60 μm, and about 40 μm andabout 60 μm. The starting melting point and the molten temperature forthis particular calcium phosphate material of the invention is 885° C.

[0032] The term “appropriate reaction temperature” includes temperaturesat which the phosphate and calcium ions can react and anneal, but arenot molten. In a further embodiment, the appropriate reactiontemperature is about 5° C. to 150° C. below the melting point of themixture. The appropriate reaction temperature may vary based on the Ca/Pratio and may also be dependent on the calcium and phosphate ionsources.

[0033] In an embodiment, the mixture is preheated to an appropriatepreheating temperature before reacting and annealing. Advantageouslyupon preheating, the mixture of calcium and phosphate ions formmanipulable paste. The paste can then be shaped (e.g., by hand or by amold) such that it can perform its intended function. Subsequent heatingto a temperature 15° C. below its starting melting point will form asolid of the desired shape.

[0034] The term “appropriate preheating temperature” includestemperatures at which the phosphate is partially condensed and forms amanipulable paste after an appropriate length of time (e.g., aboutthirty minutes or a time sufficient to form a manipulable paste). In oneembodiment, the appropriate preheating temperature is about 250° C.

[0035] In a further embodiment, the method also includes preheating themixture to 400° C. to 760° C. for at least 1 second at least once, priorto the heating the mixture to the appropriate reaction temperature. Themixture may be preheated one, two, three or more times.

[0036] In another embodiment, the reaction mixture is compressed to apressure of 10,000 psi. The reaction mixture may also be heated to 250°C. to 400° C. for an appropriate time, e.g., at least thirty minutes.

[0037] The mixture may also be molded into a shape which is advantageousfor its intended purpose. For example, the reaction mixture may beplaced into a mold prior to heating and pressed to a pressure of 100 psito 20,000 psi for at least 1 second.

[0038] The mixture may be subject to ultrasonic vibration duringcompression. Furthermore, an acid catalyst may be added to the reactionmixture. The acid catalyst may be an inorganic or organic acid.

[0039] In a further embodiment, vacuum filtration of a salt solution andelectrophoresis, may be used to remove unreacted ions and the acidcatalyst from the porous solid calcium phosphate material after thereaction and annealing step.

[0040] The calcium phosphate mixtures may be heated by any appropriatemethod known in the art. Examples of heating mechanisms include electricfurnaces, radio frequency heating, laser radiation, and microwaveradiation. As used herein, the term “furnace” is used to refer to anydevice which is capable of heating a mixture of calcium and phosphateions to a temperature lower than the molten state where the reactantsmay react.

[0041] In a further embodiment, the mixture is placed on an inertsupporting material, such as boron nitride, such that reactions betweenthe mixture and the supporting material are prevented.

[0042] The invention also pertains to a surgical implant comprising acalcium phosphate material produced by the methods of the invention. Theinvention also pertains to a calcium phosphate material produced by themethods of the invention.

[0043] In one further embodiment, the calcium phosphate material isproduced by mixing orthophosphoric acid and hydroxyapatite and rapidlyheating the mixture to 760° C., such that the mixture is dehydrated andpartially condensed. The mixture is molded under high pressure andheated to an appropriate temperature (e.g., a temperature at whichtemperature the components react but are not molten state, e.g., 15° C.below the mixture's melting point).

[0044] In a further embodiment, the bulk density of the calciumphosphate material is manipulated by applying different pressure on themixture in the mold before heating. The pressure applied to the mixturecan vary from 100 psi to 20,000 psi. The pressure on the materialconstitutes a low bulk density of about 1.00 gm/cm ³ and the 10,000 psipressure makes a material of bulk density about 2.2 gm/cm³. In otherembodiments, the calcium phosphate material of the invention has a bulkdensity of between about 1.0 gm/cm³ to about 2.5 gm/cm³, about 1.0gm/cm³ to about 2.2 gm/cm³, about 1.0 gm/cm³ to about 2.1 gm/cm³, about1.0 gm/cm³ to about 2.0 gm/cm³, about 1.0 gm/cm³ to about 1.9 gm/cm³,about 1.0 gm/cm³ to about 1.8 gm/cm³, about 1.0 gm/cm³ to about 1.7gm/cm³, about 1.0 gm/cm³ to about 1.6 gm/cm³, about 1.0 gm/cm³ to about1.5 gm/cm³, about 1.1 gm/cm³ to about 2.2 gm/cm³, about 1.2 gm/cm³ toabout 2.2 gm/cm³, and about 1.3 gm/cm³ to about 2.2 gm/cm³.

[0045] In another embodiment, acid catalysts are used to facilitate theformation of the calcium phosphate material. Acid catalysts may be fromorganic or inorganic (e.g., hydrochloric acid) sources. Acid catalystsfrom organic sources can later be oxidized into carbon dioxide andwater. Inorganic acids can be removed by water or by electrophoresis.The acid catalyst is added after the preheating stage (e.g., dehydrationand partially condensing stage) but before the heating to theappropriate reaction temperature (e.g., 15° C. below the molten state).In addition, this heating process to the appropriate reactiontemperature can be lengthened to make ensure that the organic acidcatalyst has been oxidized to carbon dioxide and water.

[0046] The unreacted soluble reactants or soluble components of thefinal product can be removed by water or they can be more efficientlyremoved by electrophoresis. Soluble unreacted inorganic acid catalystscan dissolve in water, although trapped acid in the highly porousmaterial may diffuse out of the calcium phosphate material slowly. Amore efficient way to remove the catalysts is through the use ofelectrophoresis which can actively remove the ions out of the material.Unreacted soluble reactants, or unstable final components such as, forexample, pyrophosphate, can also be pulled out of the material much moreefficiently with electrophoresis.

[0047] The calcium phosphate materials of this invention may comprise avariety of crystalline and amorphous substances. Various types ofanalyses have indicated that solid calcium phosphate materials includeapatite calcium phosphates, mono and dibasic calcium phosphates,pyrophosphates, metaphostates, polymetaphosphates, and orthophosphatespecies.

[0048] For certain uses, the porous calcium phosphate material of theinvention has several significant advantages over solid calciumphosphate materials, such as sintered hydroxyapatite. For example, theporous calcium phosphate material of the invention is more biodegradablethan the sintered hydroxyapatite and is therefore more suitable as abone substitute. The osteoclasts at the site of the transplantationactively dissolve the porous calcium phosphate material. The porouscalcium phosphate material is replaced by the real bone (deposited bythe osteoblasts), while undergoing biodegradation. Advantageously, thedegradation rate of the porous calcium phosphate material is compatiblewith the rate of regeneration, such that the replacement does not loseits function before total degradation. In addition, the highlyinterconnected porosity advantageously allows for the penetration of theosteoclasts and osteoblasts into the porous calcium phosphate materialof the invention, such that the material eventually becomes living bone.Examples of porous calcium phosphate material with interconnected poresare shown in FIGS. 1b-1 g.

[0049] In an embodiment, the porous calcium phosphate material of theinvention is produced by mixing orthophosphoric acid and hydroxyapatite.The mixture is then dehydrated and partial condensed by rapid heating toan appropriate temperature for an appropriate length of time (e.g., atemperature of about 760° C. for 30 seconds) once or repeatedly.

[0050] In another embodiment, the invention pertains to method ofproducing a porous calcium phosphate material. The method includesforming a mixture of calcium ions and phosphate ions, having a calciumto phosphorus ratio of 0.1 to 1.67, adding a gas-generating material tothe mixture, heating the mixture an appropriate reaction temperature,and cooling the mixture such that a solid, porous calcium phosphatematerial is produced. Preferably, the porous calcium phosphate materialproduced has interconnected pores. In a further embodiment, theappropriate reaction temperature is about 5° C. to 150° C. below themelting point of the mixture

[0051] To create porosity, gas-generating material may be incorporatedinto the mixture of calcium and phosphate ions. The pore size of thecalcium phosphate material may be determined by the size of the granulesof the gas-generating material. For example, to generate a calciumphosphate material with pore sizes between about 250 μm and about 400μm, the size of the granules of gas-generating material should also bebetween about 250 μm and about 400 μm.

[0052] The term “gas-generating material” includes materials thatgenerate gas when subjected temperatures below the appropriate reactiontemperature and/or at reduced pressures. Examples of gases that may begenerated by the gas-generating material include, but not limited toammonia, water, hydrogen, or carbon dioxide.

[0053] In a further embodiment, the gas-generating material generatesammonia. Examples of sources of ammonia include, but are not limited to,ammonium carbonate, ammonium bicarbonate, ammonium acetate, ammoniumhydroxide, ammonium nitrates, ammonium sulfates, ammoniumhydrogenphosphate, ammonium dihydrogeuphosphate, ammoniumfluorophosphates, ammionium citrate, ammonium hydrogencitrate, ammoniumhydrogen difluoride, ammonium hydrogen oxalate hemihydrate, ammoniumhalides, ammonium salts, ammonia anhydride, ammonia solutions, andcombinations thereof.

[0054] In another further embodiment, the gas-generating material isgenerates carbon dioxide. Examples of sources of carbon dioxide include,but are not limited to, ammonium carbonate, ammonium bicarbonate, metalcarbonates, non-metal carbonates and mixtures thereof.

[0055] For example, 15% by weight of the selected ammonium bicarbonateis mixed with the mixture of calcium and phosphate ions. The mixture isthen molded and placed in an electric furnace. Ammonium bicarbonatestarts to decompose at roughly 60° C. The heating rate is carefullycontrolled, such that the decomposition of ammonium bicarbonate does notoccur too vigorously and create cracks in the calcium phosphatematerial. For example, the heating rate may be about 0.5° C./minute andthe temperature may be held at 250° C. for 12 hours. This period of timeallows for the decomposition of ammonium bicarbonate before the highertemperature reactions of the calcium phosphate species.

[0056]FIGS. 1a-1 g show calcium phosphate materials made with no, 15%,20%, and 25% ammonium bicarbonate gas-generating materials (by weight,before the ammonium bicarbonate decomposed). FIG. 1a shows the controlcalcium phosphate material. FIG. 1b shows the calcium phosphate materialusing 15% ammonium bicarbonate with a particle size greater than 425 μm.FIG. 1c shows a calcium phosphate material made with 20% ammoniumbicarbonate, with a particle size of less than 106 μm. FIG. 1d shows acalcium phosphate material with 20% ammonium bicarbonate with a particlesize between 212-250 μm. FIG. 1e shows a calcium phosphate material madewith 20% ammonium bicarbonate, with a particle size between 250 and 425μm. FIG. 1f shows a calcium phosphate material made with 20% ammoniumbicarbonate with a particle size between 250 and 425 μm. FIG. 1g shows acalcium phosphate material made with 25% ammonium bicarbonate with aparticle size between 125 and 250.

[0057]FIG. 2 is a histogram which shows the frequency of pore diametersfor control calcium phosphate material (without gas-generatingmaterial), calcium phosphate made with 20% by weight of ammonium bycarbonate (with a particle size of 125-250 μm), and calcium phosphatematerial made with 25% by weight of ammonium carbonate with a particlesize from about 106 to about 125 μm.

[0058] The subsequent heating to a higher temperature affords the energyfor the reactive calcium phosphate species to react and a solid calciumphosphate ceramic material to be obtained after the heating process. Thecavities left behind by the decomposition of gas generating materialcreate interconnected pores within the calcium phosphate material.Mercury intrusion analysis shows the pore sizes have been significantlyenlarged compared with the native pore sizes produced by thecondensation reaction of the material. The percentage of porosity isalso more then that of the material without incorporation of the gasgenerating material.

[0059] In another embodiment, the mixture is placed into a mold andpressed to a pressure of 100 psi to 20,000 psi for at least 1 secondbefore being heated to the appropriate reaction temperature. In anotherembodiment, the mixture is subject to ultrasonic vibration bombardmentwhile in the mold.

[0060] In another embodiment, the invention also pertains to a method ofproducing a porous calcium phosphate material. The method includesmixing a gas-generating material and a calcium phosphate ceramicprecursor, heating the mixture to below the sintering temperature togenerate a gas, and sintering the calcium phosphate ceramic precursorsto make a solid material.

[0061] The term “calcium phosphate ceramic precursor” includes, forexample, monocalcium phosphate hydrate (MCP), dicalcium phosphatehydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalciumphosphate pentahydrate (OCP), tricalcium phosphate (TCP), alpha and betafrom (hydroxyapatite), pentacalcium hydroxylphosphate (HAP),tetracalcium phosphate monoxide (TCPM), calcium pyrophosphate, calciummetaphospates, polycalcium metaphospates, and combinations thereof.

[0062] In another embodiment of this invention, a similar strategy canbe applied to make artificial porosity by using chemicals capable ofbeing sublimed at elevated temperature and/or reduced atmosphericpressure. For example, H₂O ice can be sublimed at sub-zero ° C.temperate under vacuum, which process has been referred as freezedrying. Granules of selected sizes of ice can be mixed with mixture ofreactive calcium phosphate species or calcium phosphate ceramicprecursors, which is pre-chilled to sub-zero° C. The mixture can then bemolded in a mod, which is also pre-chilled to sub-zero° C., the wholeprocess would have to be conducted in a cold room of 0° C. or below toprevent melting of the ice. After the mixture has been molded, themixture block is placed in liquid nitrogen and then a flask connected tovacuum line. After 24 hours of vacuum, the ice granules inside the blockwill be sublimed, leaving cavities inside the material without residues.

[0063] In an embodiment, the invention pertains to a method of producinga porous calcium phosphate material. This method comprises subliming achemical in a reactive calcium phosphate mixture precursor, and reactingthe reactive calcium phosphate mixture, to produce a porous calciumphosphate material.

[0064] In yet another embodiment, the invention also pertains at leastin part to a method of producing a porous calcium phosphate material.The method includes subliming a chemical in one or more calciumphosphate ceramic precursor and sintering the calcium phosphateprecursor, to produce a porous calcium phosphate material.

[0065] In a further embodiment, the chemical is selected such that it iscapable of being sublimated at a temperature below 400° C. and/or at apressure of greater than 0.1 torr.

[0066] The invention also pertains, at least in part, to interconnectedporous calcium phosphate materials. The material may be generated by anymethod described herein. Advantageously, the material is capable ofosteointegration and osteoconduction. Osteointegration can be measuredas the percentage of the perimeter length of implant covered by bone, asdescribed in the Examples. In one embodiment, the amount ofosteointegration of the implant of the invention is about 5% or greater,about 10% or greater, about 11% or greater, about 12% or greater, about13% or greater, about 14% or greater, about 15% or greater, about 16% orgreater, about 17% or greater, about 18% or greater, about 19% orgreater, about 20% or greater, about 21% or greater, about 22% orgreater, about 23% or greater, about 24% or greater, about 25% orgreater, about 30% or greater, about 35% or greater, about 40% orgreater, about 45% or greater, about 50% or greater, about 55% orgreater, about 60% or greater, about 65% or greater, about 70% orgreater, about 75% or greater, about 80% or greater, about 85% orgreater, about 90% or greater, about 95% or greater, or about 100%.

[0067] In other embodiments, the calcium phosphate material of theinvention has a compression strength of about 10,000 psi or greater,about 11,000 psi or greater, about 12,000 psi or greater, about 13,000psi or greater, about 14,000 psi or greater, about 15,000 or greater,about 16,000 psi or greater, about 17,000 psi or greater, about 18,000psi or greater, about 19,000 psi or greater, about 20,000 psi orgreater, about 21,000 psi or greater, about 22,000 psi or greater, about23,000 psi or greater, about 24,000 psi or greater, or about 25,000 psior greater.

[0068] In other embodiments, the calcium phosphate material of theinvention has a bulk density of between about 1.0 gm/cm³ to about 2.5gm/cm³, about 1.0 gm/cm³ to about 2.2 gm/cm³, about 1.0 gm/cm³ to about2.1 gm/cm³, about 1.0 gm/cm³ to about 2.0 gm/cm³, about 1.0 gm/cm³ toabout 1.9 gm/cm³, about 1.0 gm/cm³ to about 1.8 gm/cm³, about 1.0 gm/cm³to about 1.7 gm/cm³, about 1.0 gm/cm³ to about 1.6 gm/cm³, about 1.0gm/cm³ to about 1.5 gm/cm³, about 1.1 gm/cm³ to about 2.2 gm/cm³, about1.2 gm/cm³ to about 2.2 gm/cm³, and about 1.3 gm/cm³ to about 2.2gm/cm³.

[0069] In other embodiments, the calcium phosphate material has aporosity of between about 20% and about 80%, about 25% and about 75%,about 30% and about 70%, about 30% and about 65%, about 35% and about65%, about 40% and about 65%, about 41% and about 65%, about 42% andabout 65%, about 43% and about 65%, about 44% and about 65%, about 45%and about 65%, about 46% and about 65%, about 47% and about 65%, about48% and about 65%, about 40% and about 64%, about 40% and about 63%,about 40% and about 62%, about 40% and about 61%, about 40% and about60%, about 40% and about 59%, and about 40% and about 58%.

[0070] The porosity can be measured by methods known to those of skillin the art, for example, by Mercury Intrusion Porosimetry (MIP). MercuryPorosimeters deliver fast, accurate pore structure data for a widevariety of materials. They are provide an automated analysis of porousmaterials with pore diameters ranging from 360 to 0.0055 μm and arecommericially available (Micromeritics, Norcross, Ga.).

[0071] In an embodiment, the reactive calcium phosphate mixtureprecursor comprises calcium phosphates, non-apatitic calcium phosphates,calcium hydroxide, calcium oxide, calcium carbonate, calcium salts,calcium halide and calcium metal, orthophosphoric acid, pyrophosphoricacids, condensed phosphates, phosphate or non-metal cations, metalphosphates, or mixtures thereof.

[0072] In an embodiment, the calcium phosphate material generated by themethods of the invention is biodegradable. In a further embodiment, thecalcium phosphate material of the invention further comprisesosteoinductive agents.

[0073] In a further embodiment, the calcium phosphate material comprisesthe calcium salt of

[0074] wherein n is from about 10 to about 1,000,000. In a furtherembodiment, n is between 50 and 1,000,000.

[0075] The term “osteoinductive agents” includes agents known in the artto enhance bone formation. Examples of such agents include, but are notlimited to osteoprogenitor cells from bone morrow or bone morphogenicproteins.

[0076] In a further embodiment, the invention pertains to a method oftreating a bone disorder in a subject. The method includes applying acalcium phosphate material of the invention to a bone of said subject,and allowing the bone to heal, such that the bone disorder of saidsubject is treated. Examples of bone disorders include fractures orother bone defects which require bone replacement. Preferably, thesubject is a mammal, e.g., a sheep, dog, cat, horse, monkey, rabbit,mouse, bear, or, preferably, a human.

[0077] The methods of the present invention produce controllableporosity within a biodegradable calcium phosphate material which issuitable for certain applications where high porosity is favored. Thehigher porosity has been reported to be beneficial for the infiltrationof osteoclasts and osteoblasts into the ceramic material, and whichfacilities the turn over rate of the biodegradable ceramic that closelyresembles the real bone.

[0078] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments and methods described herein. Such equivalents areintended to be encompassed by the scope of the following claims. Allpatents, patent applications, and literature references cited herein arehereby expressly incorporated by reference.

EXEMPLIFICATION OF THE INVENTION

[0079] The invention is further illustrated by the following exampleswhich should not be construed as limiting.

Example 1

[0080] 30 gm of hydroxyapatite (from Mutter Chemical Company under thename of tricalcium phosphate, Ca₁₀(PO₄)₆(OH)₂) was added to 32.5 ml of85% orthophosphoric acid in a porcelain bowl. The mixture was ground andheated at 760° C. for 30 seconds. This process was repeated twice. Themixture was cooled down and placed in a stainless mold. A hydraulicpress was used to compress the powder mixture in the mold to about10,000 psi for about 30 seconds and then removed from the mold. Thepressed mixture was then heated in an electric furnace on an inert boronnitride support. The heating rate was about +1.67° C./minute and thetemperature was held at 870° C. (e.g., 20° C. below 890° C., thebeginning of the molten state of the reacting mixture) for 12 hours.After the 12 hours' incubation, the calcium phosphate block was cooleddown slowly at the rate of −1.67° C./minute to room temperature.

[0081] Qualitative analysis of the block showed that the calciumphosphate material contained 19.65% calcium, 30.75% phosphorus, lessthan 0.1% nitrogen and less then 0.1% hydrogen. The infrared spectrumsignature indicated the existence of polymetaphospate in the solid andpowder X-ray diffraction showed a mixture of other calcium phosphatespecies.

[0082] The bulk density of the material was about 1.46 cm/cm³. Theapparent density was about 300 gm/cm³. The compression strength of themixture was about 20,000 psi. The porosity of the material wasdetermined to be around 50% with an average pore size of 50 μm, and thesurface area is about 0.019 m2/g. Vacuum infiltration withpolymethacrylate and subsequent removal of the calcium phosphatematerial with hydrofluoric acid created a negative representation of theporosity showing highly interconnectivity of the pores inside thematerial. The calcium to phosphorus ratio of this material was around0.486.

Example 2

[0083] 30 gm of hydroxyapatite (from Mutchler Chemical, Ca₁₀(PO₄)₆(OH)₂)is added to 32.5 ml of 85% orthophosphoric acid in a porcelain bowl. Themixture is ground and heated at 760° C. for 30 seconds and this processis repeated twice, before being cooled to room temperature. The mixtureis pressed under 10,000 psi for about 30 seconds. Then the mixture isheated in an electric furnace at a rate of 0.5° C./minute and thetemperature is held at 250° C. for 30 minutes. After the 30 minutes'incubation, the temperature is cooled down to room temperature. Theresulting mixture is a manipulable white-colored paste and which can beshaped with hand or placed in a mold. Then, the shaped paste is placedon an inert boron nitride surface in an electric furnace and thetemperature is raised at the rate of 1.67° C./minute to 870° C. (e.g.,20° C. below the beginning of the molten state of the reacting mixture).The temperature is then held at 870° C. for another 12 hours. At the endof the 870° C. incubation, the temperature is gradually reduced to roomtemperature at a rate of 1.67° C./minute.

[0084] Qualitative analysis of the block shows the calcium phosphatematerial contains 19.65% calcium, 30.75% phosphorus, less than 0.1%nitrogen and less then 0.1% hydrogen. Infrared spectrum signatureindicates the existence of polymetaphospate in the solid and powderX-ray diffraction also shows a mixture of other calcium phosphatespecies in the composition.

[0085] The bulk density of this material is about 1.46 cm/cm³. Theapparent density is about 3.00 gm/cm³. The compression strength of themixture is about 20,000 psi. Mercury intrusion shows the porosity of thematerial is about 50%, with an average pore size 50 μm. The mercuryintrusion also shows that the surface area of the material is about0.019 m²/g. Vacuum infiltration with polymethacrylate and subsequentremoval of the calcium phosphate material with hydrofluoric acid createsa negative representation of the porosity showing highlyinterconnectivity of the pores inside the material. The calcium tophosphorus ratio of this material is around 0.486.

Example 3

[0086] Using the method described in Example 1, the pressure applied tothe mixture while being placed in a stainless mold is varied. Thepressure applied to the mold ranged from about 100 psi to 20,000 psi.The volume of the resulting mixture varies corresponding to the appliedpressure. After the subsequent heating in the furnace according to thesame procedure described in Example 1, the bulk density of the pressuredmixture ranged from around 1.0 gm/cm³ to 2.2 gm/cm³.

Example 4

[0087] 30 gm of hydroxyapatite (from Mutchler Chemical Company under thename of tricalcium phosphate, Ca₁₀(PO₄)₆(OH)₂) is added to 32.5 ml of85% orthophosphoric acid in a porcelain bowl. The mixture is ground andheated at 760° C. for 30 seconds three times. The mixture is cooled downand 1 ml of 0.1M HCl is added to the mixture and the resulting mixtureis heated to 200° C. for five minutes. The resulting mixture is thenplaced in stainless mold. A hydraulic press is used to compress thepowder mixture in to the mold to about 10,000 psi for about 30 seconds.While pressing the mixture in the mold, a source of ultrasound, such asa ultrasound probe, may be applied on the stainless mold to help packingthe mixture inside the mold. The block of mixture is then removed fromthe mold. The pressed mixture is then heated in an electric furnacesitting on an inert boron nitride supporting material. The heating rateis about +1.67° C./minute and the temperature is held at 870° C. (e.g.,20° C. below 890° C., the beginning of the molten state of the reactingmixture) for 12 hours. After the 12 hours' incubation, the reactedcalcium phosphate block is cooled down slowly at the rate of −1.67°C./minute to room temperature. The acid is later removed byelectrophoresis described in Example 2.

Example 5

[0088] With the same procedure described in either Example 1 or 3, afterthe mixture has been heated under 870° C. for 12 hours, the mixture iscooled down and then placed in a vacuum flask, which is connected to avacuum line. The atmospheric pressure inside the flask is then reducedto 25 microns of mercury. 0.1 NaCl is then injected into the flask andthe material is totally submerged in the salt solution. The material isthen placed in a electrophoresis cell and 150 volts of voltage isapplied to the cell for 30 minutes. The material is then rinsed out in 1gallon of distilled water twice to remove the salt solution.

Example 6

[0089] 30 gm of hydroxyapatite (from Mutchler Chemical Co.,Ca₁₀(PO₄)₆(OH)₂) is added to 32.5 ml of 85% orthophosphoric acid in aporcelain bowl. The mixture is ground and heated at 760° C. for 30seconds three times. The mixture is cooled down to room temperature.Particles of ammonium bicarbonate are selected by sieves of pore sizesbetween 250 μm and 400 μm. 1.5 parts by weight of the ammoniumbicarbonate of selected particle sizes are mixed with 8.5 parts of thecalcium phosphate mixture. This mixture is pressed under 10,000 psi for30 seconds and then heated in an electric furnace. The heating rate is0.5° C./minute and the temperature is held at 250° C. for 12 hours.After the 12 hours' incubation the temperature is raised at the rate of1.67° C./minute of 870° C., 20° C. below the beginning of the moltenstate of the reacting mixture, and the temperature stays at 870° C. foranother 12 hours. At the end of 870° C. incubation, the temperature isgradually cooled down to room temperature at the rate of 1.67°C./minute.

[0090] The bulk density of this material is about 1.3 gm/cm³. Theapparent density is about 3.10 gm/cm³. The compression strength of themixture is about 11,000 psi. Mercury intrusion shows the its porosity isaround 58%, with average pore size 130 μm. Vacuum infiltration withpolymethacrylate and subsequent removal of the calcium phosphatematerial with hydrofluoric acid creates a negative representation of theporosity showing highly interconnectivity of the pores inside thematerial.

Example 7

[0091] Using apatitic or non-apatitic calcium phosphate ceramicprecursors to make sintered form of solid material, these precursors canbe mixed with certain weight percentage of ammonium bicarbonate tocreate controlled porosity of desired sizes. The weight percentage canbe varied according to the need. A 15 parts of selected pore sizes ofsolid ammonium bicarbonate are mixed with 85 parts of alpha formtricalcium phosphate. The mixture is then pressed to make solid block.This block is then placed in an electric furnace and the temperate israise slowly at the rate of 0.5° C./minute to 250° C. and stays at 250°C. for 12 hours. After the 12 hours incubation, the temperature of thefurnace is raised to the sintering temperature of the alpha tricalciumphosphate.

Example 8

[0092] To control porosity using chemicals capable of sublimation alphaform tricalcium phosphate, or other calcium phosphate ceramicprecursors, can be mixed with certain weight percentage of water ice at−20° C. to create controlled porosity of desired sizes. The alpha formtricalcium phosphate ceramic precursor needs to be pre-chilled in a coldroom at 0° C. or below. The weight percentage can be varied according tothe need. A 15 parts of selected pore sizes of solid water ice are mixedwith 85 parts of alpha form tricalcium phosphate. The mixture is thenpressed in a pre-chilled mold below 0° C. to make solid block of theceramic precursor. This block is then placed in liquid nitrogen andsubsequently in a container connected to a freeze drying apparatus. Thetemperature is left to raise slowly as the vacuum at 200 micron Mercuryis applied to the material. After the 24 hours incubation, thedehydrated material is then placed in an electric furnace and thetemperature of the furnace is raised to the sintering temperature of thefurnace is raised to the sintering temperature of the alpha tricalciumnphosphate.

Example 9

[0093] This example shows the use of the calcium phosphate material forspinal fusion in sheep.

[0094] Posterior spinal fusions are commonly performed for a widevariety of disorders including deformities, tumors and fractures. Largequantities of bone graft are often necessary. The standard procedure isto harvests autologous bone graft from the iliac crest. This techniquecarries a significant morbidity and complication rate, often involving asecond incision with the attendant risks of bleeding, infection andpersistent donor site pain. Furthermore, adequate graft may not bealways obtainable, especially following previous spinal operations, inosteoporotic patients with poor bone stock or treating patients withmetastatic tumor.

[0095] Allograft bone has been used as an alternative. Allografts maynot be as readily available, are not as effective as a posterior onlaysubstance, are costly to procure and have the potential for diseasetransmission. Due to these shortcomings, researchers have attempted todevelop a bone graft substitute. The ideal synthetic bone replacementwould be mechanically comparable in strength to autologous bone, beeasily fashioned for implantation and possess the ability to bebiologically incorporate. Implant materials composed of calciumphosphate are probably the most biocompatible synthetic hard tissueimplant materials presently available. These ceramics are available ashydroxyapatite, tricalcium phosphates, or combinations of the two(porous, nonporous implants or granular particles) Tricalcium phosphateis porous and rapidly degraded. It is also mechanically weaker thanhydroxyapotite. Replamine form hydroxyapatite is formed by ahydrothermal exchange process using coral (porites) as a porous calciumcarbonate skeleton. Limitations include incorporate conversion of thecarbonate, variable sizes and shapes of the original coral exo-skeletonand this material is also structurally weak compared to biological bone.

MATERIALS AND METHODS

[0096] Implant Description

[0097] Highly porous calcium polyphosphate material with a calciumphosphate ratio of 0.55 was fabricated from this animal study in matchstick shapes. Pore diameter ranged up to 200 microns. The material wassterilized using radiation techniques.

OPERATIVE TECHNIQUE

[0098] 12 conditioned adult male sheep were used in this example. Aftergeneral endotracheal anesthesia, each animal was placed prone on theoperating table, prepped and draped in sterile fashion. Two midlinelongitudinal incisions were made. An incision between L1-2 was carrieddown to the spinous process. The midline spinous process and ligamentswere preserved and the dissection was carried laterally out to the tipsof the transverse process, between L1 and L2. Decortication andfacetectomy was accomplished using gauges and curettes. In similarfashion, a separate incision was made at the L4-5 location anddissection carried down to the tips of the transverso process of L4 and15 bilaterally and similar decortication and facetectomy accomplished.Cortical cancerous bone graft was harvested from both iliac crests intwo separate incisions, using ostotomics and curettes. This autologousbone graft was then fashioned into small bony strips and bone graft wasthen implanted at the L1-L2 level, bone graft being placed bilaterallyin symmetrical fashion between the transverse processes of L1 and L2. Asimilar quantity and size of calcium phosphate bioceramic was placedbetween the transverse processes of the L4-5 lumbar segment in similarfashion. Furthermore, calcium phosphate bioceramic match stick materialwas used to fill the void created over the left iliac crest which wasthen closed in standard fashion with vinyl sutures in layers. The rightiliac crest donor site was closed leaving the iliac crest donor sitevoid unfilled. The midline incisions were closed in similar fashion. Theprocedure was repeated for the other animals using alternate levels L1-2vs. L4-5. (Calcium polyphosphate graft placed at L1-2 and autologousbone at L4-5.)

[0099] The animals were housed in the intensive care unit in individualpens. Prophylactic antibiotics were administered for 24 hours. The sheepwere allowed to weight bear immediately. Postoperative analgesia wasadministered consisting of Bupernorphine 0.005 mg to kg q. 4-6 hours forpain. The animals were killed after six months by barbiturate overdose.The lumbar spine motion segments and iliac crests were harvested andcleaned of all soft tissues.

MANUAL PALPATION

[0100] At the time of harvest, the lumbar spines were manually palpatedat the level of the fused motion segment, compared to the levels of theadjacent motion segments proximal and distal. This simulated fusionexploration and palpation in humans is considered the gold standard fordistinguishing nonunions and solid fusions. These motion segments weregraded as solid or not solid. Only levels grades as solid wereconsidered to be fused.

RADIOGRAPHIC ANALYSIS

[0101] Posterior/anterior radiographs were made and multiplane CT scanswere then performed of all motion segments. These radiographs were thenreviewed and the fusions were graded as solid or not solid based on thepresence of continuous trabeculac within the intertransverse fusionmass.

BIOMECHANICAL TESTING

[0102] Nondestructive cyclic testing was performed with an 8 by 8 bionichydraulic material testing machine (materials testing systems,Minneapolis, Minn.) on four axis, (flexion, extension, right lateralbending and left lateral bending). A ramp made in the shape of atriangle wave of 0.1 hertz was applied ten times, data was taken duringthe last cycle. Testing was performed using a 4 point bending model,intervertebral displacement was measured by an extensometer mountedanteriorly across the disc space at the level of fusion. Additionally,lumbar motion segments from sheep of similar size, age and weight werecompared as a control group.

LIGHT MICROSCOPIC ANALYSIS

[0103] The harvested spine specimens and iliac crest were fixed in 10%formalin. They were cut in half longitudinally in the sagittal plane andsagittal sections were sections were prepared. Undecalcified sectionswere dehydrated, infiltrated and imbedded in technovit basedmethylmethacrylate. Using a water cooled diamond saw, sectionsapproximately 150-200 microns in thickness were prepared. These werehand ground to approximately a thickness of 320 microns using siliconcartridge paper immersed in water and stained using a modified McNeals(tetrachrome stain). Sections were submitted from back scatter electronmicroscopy. This technique was used to analyze the volume fraction ofsoft tissue, bone, implant and osteointegration (percentage of theperimeter length of implant covered by bone) and compare the relativeamounts of soft tissue and calcified matrix in the sections.

RESULTS

[0104] Mortality and Complications

[0105] All sheep tolerated the surgical procedure well, they wereambulating and gaining weight postoperatively. No infections occurred.One animal was euthanized at one week postoperatively due touncontrollable pain probably from the iliac crest donor site. There wasno neurological deficit noted. One other animal dies six weeks aftersurgery by an unrelated accident. The pre-operative morbidity rate was16% (two deaths out of twelve sheep).

[0106] Gross Inspection/Palpation/Radiographs

[0107] Manual palpation of the fused and adjacent unfused segments wereperformed in all animals at the time of harvest. The fusion massesappeared larger in the calcium polyphosphate bioceramic levels comparedto the autologous grafted segments. The average volume beingapproximately 72 cm³ vs. 43 cm³, that is difference of 29.6 cm³ which issignificant (P value 0.0145). A fibrous membrane appeared to encapsulatethe fusion masses more noticeable on the calcium polyphosphatebioceramic fused segments compared to the autologous grafted segments.There was no evidence of gross inflammation. One of the spines developeda nonunion at both the autologous bone grafted level and at the calciumpolyphosphate bioceramic grafted level. On direct inspection andpalpation, one other nonunion was noted at a calcium polyphosphatebioceramic level. All of the remaining seventeen motion segmentsappeared to be successfully fused.

[0108] Radiographs confirmed bony trabeculation crossing the fusion massin all the unions. CT scans demonstrated incorporation of the bioceramicmatch sticks into the fusion mass. The ceramic material lying furtheraway from the bony surface of the lamina appeared to have more softtissue interposition and variable bony ingrowth. The CT scans alsoconfirmed the size of the fusion masses being larger in the bioceramiclevels when compared to autologous levels.

BIOMECHANICAL TESTING

[0109] The slopes of the force vs. displacement and the force vs. straincurves were calculated for each of the spine fusion segments analyzed.More variation appeared to occur in the slope of the force vs. straindata reflecting probable variations in the connection of theextensometer used to measure strain. Good results were seen with theforce vs. displacement data reflecting direct measurement of the loadsite displacement in the MTF fixture during the spine testing. Comparingthe upper (L1-L2) and the lower (L4-L5) fusion segments showed nostatistical significant difference. The slope data was also analyzed todetermine if the autologous and bioceramic fusion segments werecomparable. Again, there was no statistical significant differencebetween the two. Both the autologous and bioceramic spines had higherslopes when compared with the unfused controlled segments in all bendingmodes tested. All of these variations were statistically significant (p,0.05). One of the autologous and two of the bioceramic spinal segmentsappeared to be notiunions showing very low values for the slope of theforce vs. displacement curve in all four bending modes. This reconfirmedthe findings on direct manual palpation.

[0110] Light Microscopy and Backscatter Electron Microscopy Dystrometry

[0111] A dense collagenenous connective tissue with vascular capsule wasencountered on the surface of the fusion masses using the calciumpolyphosphate bioceramic. There was no evidence of an inflammatoryresponse nor resorption of the ceramic. Tremendous woven bone andosteoid was seen permeating between the ceramic material. Furthermore,proteinaceous material was seen within the ceramic pores of the materialitself. The SEM backscatter studies confirmed ingrowth of woven boneinto the porous implant matrix. The average new bone seen was 35.47%.The degree of osteo integration was also calculated by this method anddetermined to be on average 14.47%.

[0112] The model used in this example is similar to the posterolateralintertransverse fusion model used in humans. Two separate incisions wereutilized avoiding the risk of contamination between the two levels anddiminishing the amount of soft tissue stripping that occurred.Furthermore, no internal fixation was utilized. The calciumpolyphosphate material graft was used on its own without osteo inductiveagents such as bone marrow, bone morphogenic proteins or electricalstimulation. In this regard, the results of this example are better thanone might expect when one considers the challenging environment imposedon the artificial graft material. It is known that when using ceramics,it is critical to have direct apposition of the material to the hostbone, that the host bone is viable and that the interface between theimplant and the artificial bone by stabilized avoiding macro motion. Asmentioned, this example did not use internal fixation and thereforerigid fixation was not accomplished and yet acceptable fusion levels didoccur. The calcium polyphosphate bioceramics is an osteo-conductiveagent and a scaffolding for bony ingrowth. The CT scan studies andhistology studies confirmed that more bony ingrowth occurred near thesurface between the implant and the underlying host lamina bone, whilemore soft tissue ingrowth was seen between the ceramic strips lyingfurther away from the host bone as described by Booker. When oneconsiders this challenging environment, the nonunion rate of three outof 20 segments fused is an acceptable range (compared to human clinicalstudies). It is of interest that two of the nonunions occurred in thesame animal at an autologous level and at the bioceramic level.

[0113] The histological results confirmed bony ingrowth between and intothe artificial material. The backscatter electron studies confirmingrowth to be an average of 35.47%, which is comparable to otherstudies. The biomechanical studies confirmed the strength of the fusionmasses to be comparable between the artificial bone and the autologousbone levels. It is possible, though, that more remodeling occurred atthe autologous fusion segment leveis compared to the calciumpolyphosphate bioceramic levels as no evidence of resorption of theceramic was noted and the average size of the fusion mass appearedlarger in the artificial bone level compared to the autologous level, adifference of approximately 29.6 cm³. The ceramic has been noted toslowly resorb with time and it would be of interest to assess thisimplant material over a longer period.

[0114] The calcium polyphosphate material is noted to be much harderthan other ceramics currently available and felt to posses strengthcomparable to autologous bone. The advantage of the calcium phosphatematerial of the invention is more likely to be noted when used as astructurally supportive material in situations under compression such asanterior spinal column reconstructions.

[0115] In conclusion, this example shows that a fusion mass can besuccessfully created with the calcium polyphosphate material of theinvention as an osteo-conductive scaffold for new bone ingrowth.Furthermore, the fusion masses are mechanically comparable to theautologous levels. Both the riographic and histolotic evidence of bonyingrowth occurred and are comparable to other studies using artificialbone implants. No soft tissue inflammatory reaction occurred.

1. A method of producing a porous calcium phosphate material,comprising: forming a mixture of calcium ions and phosphate ions havinga calcium to phosphorus ratio of 0.1 to 1.67; heating said mixture to anappropriate reaction temperature; and cooling the reaction mixture, suchthat a porous calcium phosphate material is produced.
 2. The method ofclaim 1, wherein said appropriate reaction temperature is about 5° C. to150° C. below the melting point of the mixture.
 3. The method of claim1, further comprising preheating said mixture to 400° C. to 760° C. forat least 1 second.
 4. The method of claim 3, wherein said mixture ispreheated to 400° C. to 760° C. for at least 1 second two or more times.5. The method of claim 1, further comprising compressing said mixture toa pressure of 10,000 psi.
 6. The method of claim 1, wherein said ratioof calcium to phosphate ions is about 0.40 to about 0.60.
 7. A surgicalimplant comprising a calcium phosphate material produced by the methodof claim
 1. 8. A calcium phosphate material produced by the method ofclaim
 1. 9. A method of producing a porous calcium phosphate materialcomprising: forming a mixture of calcium ions and phosphate ions; addinga gas-generating material to said mixture; heating said mixture anappropriate reaction temperature; and cooling said mixture such that asolid, porous calcium phosphate material, is produced.
 10. The method ofclaim 9, wherein said gas-generating material is a source of ammoniumions selected from the group consisting of ammonium carbonate, ammoniumbicarbonate, ammonium acetate, ammonium hydroxide, ammonium nitrates,ammonium sulfates, ammonium hydrogenphosphate, ammoniumdihydrogenphosphate, ammonium fluorophosphates, ammonium citrate,ammonium hydrogencitrate, ammonium hydrogen difluoride, ammoniumhydrogen oxalate hemihydrate, ammonium halides, ammonium salts, ammoniaanhydride, ammonia solutions, and combinations thereof.
 11. A surgicalimplant comprising a calcium phosphate material produced by the methodof claim
 9. 12. A calcium phosphate material produced by the method ofclaim
 9. 13. A method of producing a porous calcium phosphate materialcomprising: mixing a gas-generating material and a calcium phosphateceramic precursor; heating said mixture to below the sinteringtemperature to generate a gas; and sintering the calcium phosphateceramic precursors to make solid ceramic materials, such that a porouscalcium phosphate material is produced.
 14. The method of claim 13,wherein said calcium phosphate ceramic precursor is monocalciumphosphate hydrate (MCP), dicalcium phosphate hydrate (DCPD), dicalciumphosphate anhydrous (DCPA), octacalcium phosphate pentahydrate (OCP),tricalcium phosphate (TCP), alpha and beta from (hydroxyapatite),pentacalcium hydroxylphosphate (HAP), tetracalcium phosphate monoxide(TCPM), calcium pyrophosphate, calcium metaphosphates, polycalciummetaphospates, or combinations thereof.
 15. A method of producing aporous calcium phosphate material comprising subliming a chemical in areactive calcium phosphate mixture precursor, and reacting the reactivecalcium phosphate mixture, to produce a porous calcium phosphatematerial.
 16. A method of producing a porous calcium phosphate materialcomprising subliming a chemical in one or more calcium phosphate ceramicprecursor and sintering the calcium phosphate precursor, to produce aporous calcium phosphate material.
 17. A calcium phosphate material,wherein said material is synthetic and comprises pores, wherein saidpores have an average size between about 20 μm and about 200 μm.
 18. Thecalcium phosphate material of claim 17, wherein said material has a bulkdensity of about 1.0 gm/cm³ to about 2.5 gm/cm³.
 19. The calciumphosphate material of claim 17, wherein said material has a porosity ofabout between about 20% and about 80%.
 20. The calcium phosphatematerial of claim 17, wherein said material has interconnected pores.21. The calcium phosphate material of claim 17, wherein said materialhas a compression strength of about 10,000 psi or greater.
 22. A methodof treating a bone disorder in a subject, comprising applying a calciumphosphate material, to a bone of said subject, such that said bonedisorder of said subject is treated, wherein said material is porous andsynthetic.
 23. A calcium phosphate material, comprising the calcium saltof:

wherein n is an integer between 10 and 1,000,000.